1. Technical Field
The present disclosure pertains to antisolvent crystallization and, more particularly, to antisolvent crystallization performed in porous hollow fiber devices. More specifically, the present disclosure is directed to antisolvent crystallization, i.e., mixing of two miscible liquids/solutions, in porous hollow fiber devices that facilitate advantageous levels of radial mixing not present in conventional tubular devices.
2. Background Art
Crystallization and precipitation processes are widely used in the chemical and pharmaceutical industries for the separation, purification and/or production of bulk or fine chemicals. The role of crystallization in the production of crystalline commodity products, such as bulk chemicals, sugar, salt and many fertilizers, is important and the process itself is reasonably well established and understood, as summarized in the related literature. In recent years, the importance of fine chemicals and specialty products and their high added value have shifted interest in crystallization research towards organic materials, an area relatively undeveloped until the late 1980's.
The pharmaceutical industry produces a range of crystalline products of high value. It is estimated that over 90% of all pharmaceutical products contain an active ingredient in particulate form, while 65% of FDA-approved new drug entities in 2000 and 2001 were in solid form. Properties of interest include: a narrow crystal size distribution (CSD), crystal shape/habit and purity. In some embodiments, small crystal sizes may be preferred, since smaller particles may dissolve more readily according to the Noyes-Whitney equation and can increase the speed of action and bioavailability of the drug. Such properties are determined from a variety of factors, such as crystallization technique employed, type and size of equipment used, operating conditions, and choice of solvent.
Crystallization is generally carried out in stirred vessels, whether in batch or continuous processes. Despite the fact that industrial crystallizers can be successfully operated, there is often considerable variability in the crystal size distribution. Further, due to imperfect mixing and non-uniform supersaturation conditions inside the crystallizer, there may be issues in obtaining a small mean crystal size. Non-uniform supersaturation can lead to uncontrolled nucleation and non-uniform growth, effects that are clearly undesirable.
Imperfect mixing is an inherent characteristic of Mixed Suspension Mixed Product Removal (MSMPR) crystallizers. Indeed, imperfect mixing has been repeatedly reported in the literature for industrial crystallizers where performance is frequently characterized by segregation effects. Imperfect mixing is also not uncommon in small scale applications. For example, large differences in CSD characteristics of samples obtained from different points of a 10 L laboratory cooling crystallizer have been reported for potassium nitrate. Upon scale-up, such mixing problems can become dominant, leading to a broad CSD and a final product that does not meet its initial specifications.
Scale-up problems are more pronounced and difficult to address for antisolvent crystallization processes. In this case, effective mixing is needed at the addition point and thereafter. Micromixing and macromixing issues should also be addressed to achieve effective antisolvent crystallization. Often neglected, mesomixing can also be an important factor in the design and operation of a crystallizer, particularly if the feed point is above surface and the induction time is small.
Two approaches have generally been followed to overcome the above-mentioned shortcomings. The first approach for improving existing facilities involves the application of in situ monitoring techniques that can lead to and facilitate better prediction and control of the applied supersaturation, which can translate to better control of the final CSD. This approach to in situ monitoring has become popular, particularly in the pharmaceutical industry where the Process Analytical Technology (PAT) initiative is expected to transform the way the process is operated. However, as previously noted, well-mixed crystallizers are intrinsically inclined towards a spectrum of local conditions in time and space and, consequently, a relatively broad CSD.
The second approach involves development of new crystallization techniques where supersaturation can be created and depleted on a microscale, resulting in a narrow CSD and a small crystal size. An example of this second approach is an impinging-jet mixer technique, where two high velocity streams are brought into contact to effect high nucleation rates, followed by growth in a well-mixed vessel or a tubular precipitator. Although this technique can result in narrow CSDs with a small crystal size, it has certain limitations. For example, the impinging-jet mixer technique often suffers from jet alignment problems and its applicability is limited to streams with a viscosity ratio smaller than 3.5, since mixing is poor for larger values. Another technique suitable for the production of pharmaceutical solids is spherical crystallization for which only the goal of a narrow CSD is obtained. Spherical crystallization generally produces crystals that are spherical agglomerates of relatively high porosity, consisting of smaller, usually needle-like crystals. Other approaches undertaken include emulsion crystallization and precipitation with supercritical fluids. The latter technique shows promising results, although it has not yet been commercialized.
The use of polymeric membranes in flat or hollow fiber form as a means to induce crystallization has lately gained renewed interest. The observation of crystal formation on the surface of polymeric membranes is as old as the process of reverse osmosis (RO). An early study of reverse osmosis as a crystallization technique was performed by Azoury et al. [See, Azoury et al., “Crystallization processes using reverse osmosis,” Journal of Crystal Growth, 79, 654-657 (1986); Azoury et al., “Habit modifiers of calcium oxalate crystals precipitated in a reverse osmosis system,” Journal of Crystal Growth, 76, 259-262 (1986); Azoury et al., “Calcium oxalate precipitation in a flow system: An attempt to simulate the early stages of stone formation in the renal tubules,” Journal of Urology, 136(1), 150-153 (1986); and Azoury et al., “Generation of supersaturation using reverse osmosis,” Chemical Engineering Research & Design, 65, 342-344 (1987).]
In particular, Azoury et al. studied the precipitation of calcium oxalate in hollow fiber reverse osmosis modules to simulate the early stages of stone formation in renal tubules. They reported mean crystal sizes ranging from 3.9-5.1 μm, while the standard deviation (SD) of the mean size was between 0.3-0.5 μm, resulting in a coefficient of variation (CV) of only 10%. Calcium oxalate is a sparingly soluble system; hence, a low mean size and coefficient of variation should be anticipated. However, the SD and CV values achieved in these studies are extremely low and indicative of the level of supersaturation generation and control that hollow fiber membrane devices can achieve. Azoury et al. also reported that about 10% of the formed crystals remained inside the reverse osmosis module. Since the concentration of calcium oxalate in the feed was low, it seems that scaling problems will be more severe for a readily soluble system. This would result in pore blockage and consequently a reduction in the flux and the generated supersaturation.
Membrane distillation, which is a solvent removal method like reverse osmosis, was used recently for crystallization. [See, Curcio et al., “Membrane Crystallizers,” Industrial & Engineering Chemistry Research, 40, 2679-2684 (2001); Curcio et al., “Membrane crystallization of macromolecular solutions,” Desalination, 145, 173-177 (2002); Curcio et al., “Recovery of fumaric acid by membrane crystallization in the production of L-malic acid,” Separation and Purification Technology, 33, 63-73 (2003); and Curcio et al., “A new membrane-based crystallization technique: tests on lysozyme,” Journal of Crystal Growth, 247, 166-176 (2003).] In membrane distillation, the solvent (water) is removed by evaporation through the pores of a hydrophobic membrane. Curcio et al. reported results for an experimental configuration where a hollow fiber membrane device was used to create uniform supersaturation, while crystallization took place in a magma circulating crystallizer. Sodium chloride was studied and relatively narrow CSDs were obtained; CV values between 42-57% were reported, representative of the values obtained in magma crystallizers. However, flux declined with time due to pore blockage.
Better results in terms of flux decline were reported by Curcio et al. in a later study of fumaric acid crystallization in aqueous L-malic acid solutions. However, the lower flux decline can be easily attributed to the much lower solubility of fumaric acid as compared to NaCl. The reported CV values of around 40% were similar to the previous NaCl study. Membrane distillation was also applied to the growth of single protein crystals suitable for X-ray diffraction measurements. This technique utilizes both flat and hollow fiber membranes and is also suitable for the determination of the crystallization kinetics. A similar technique based on reverse osmosis membranes, i.e., osmotic dewatering, has been proposed for the same purpose. [See, Todd et al., “Application of osmotic dewatering to the controlled crystallization of biological macromolecules and organic compounds,” Journal of Crystal Growth, 110, 283-292 (1991).]
Membrane reactors were also tested recently for the precipitation of barium sulfate. [See, Zhiqian et al., “Synthesis of nanosized BaSO4 particles with a membrane reactor: Effects of operating parameters on particles,” Journal of Membrane Science, 209, 153-161 (2002).] Ultrafiltration hollow fiber membranes of various molecular weight cut off (MWCO) sizes were tested. In this configuration, one of the reactants (Na2SO4) was introduced to the shell side, which is kept at a higher pressure relative to the lumen side, and passes through the membrane to the lumen side. On the lumen side, the Na2SO4 reacts with BaCl2 to form barium sulphate. Nanosized particles having a primary size of about 70 nm were produced with the smaller MWCO membranes. However, no quantitative CSD information was given and particle aggregation was evident in the transmission electron microscopy images presented. Agglomeration was found to increase with MWCO due to the transmembrane flux increase caused by the larger pores. Fouling problems were also reported which, due to the low reactant concentrations, must be more pronounced at higher concentrations.
Zarkadas and Sirkar recently proposed a new cooling crystallization technique based on solid (nonporous) hollow fibers. [See, Zarkadas et al., “Solid Hollow Fiber Cooling Crystallization,” Industrial & Engineering Chemistry Research, 43(22), 7163-7180 (2004).] This technique was applied to both inorganic and organic systems, including a pharmaceutical compound. A combination of a solid hollow fiber crystallizer with a mixing device downstream provided the most successful results. For an aqueous potassium nitrate system, this design provided crystal size distributions with 3-4 times smaller mean sizes compared to those obtained in MSMPR crystallizers. In addition, the nucleation rates achieved were 2-3 orders of magnitude higher. Experimental runs with aqueous paracetamol (4-acetamidophenol) solutions showed that a solid hollow fiber crystallizer (SHFC) static mixer assembly can be operated successfully up to 30-40° C. below published data for the metastable zone limit, a capability non-existent in industrial cooling crystallizers. [See, Zarkadas et al., “Cooling Crystallization of Paracetamol in Hollow Fiber Devices,” Industrial and Engineering Chemistry Research, 46, 2928-2935 (2007).] This ability allows the achievement of very high nucleation rates and the decoupling of nucleation and growth, an opportunity offered currently only by impinging jet mixers for antisolvent crystallization.
Despite efforts to date, a need remains for crystallization systems and methods that offer enhanced performance and that may be scaled up to industrial scale while maintaining superior operational performance and yielding crystals having desirable physical properties. These and other needs are satisfied by the systems and methods disclosed herein, as will be apparent from the description which follows.